Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists

ABSTRACT

This invention relates to a method for eating a subject with irritable bowel syndrome (“IBS”) which comprises long-term administration of an opioid receptor antagonist at an appropriately low dose which will selectively antagonize excitatory opioid receptor functions, but not inhibitory opioid receptor functions, in myenteric neurons in the intestinal tract as well as in neurons of the central nervous system (“CNS”). The administration of the opioid receptor antagonist at a low dose enhances the potency of the inhibitory effects of endogenous opioid peptides present in the intestinal tract and the CNS, thereby reducing abdominal pain and stool frequency resulting from abnormally supersensitized excitatory opioid receptor functions. The invention also relates to a composition for treating a subject with IBS, which comprises an effective dose of an opioid receptor antagonist, and a pharmaceutically acceptable carrier.

FIELD OF THE INVENTION

This invention relates to a method for treating a subject with irritablebowel syndrome (“IBS”) which comprises administering a low dose of anopioid receptor antagonist to the subject. Specifically, this inventionrelates to a method for treating a subject with IBS by the long-termadministration of an opioid receptor antagonist at an appropriately lowdose which will selectively antagonize excitatory opioid receptorfunctions, but not inhibitory opioid receptor functions, in myentericneurons in the intestinal tract as well as in neurons of the centralnervous system (“CNS”). The administration of the opioid receptorantagonist at a low dose enhances the potency of the inhibitory effectsof endogenous opioid peptides present in the intestinal tract and theCNS, thereby reducing abdominal pain and stool frequency resulting fromabnormally supersensitized excitatory opioid receptor functions. Theinvention also relates to a composition for treating a subject with IBS,which comprises an effective dose of an opioid receptor antagonist, anda pharmaceutically acceptable carrier.

BACKGROUND OF THE INVENTION

Irritable bowel syndrome is a functional bowel disorder in whichabdominal pain is associated with defecation or a change in bowel habit.IBS has elements of an intestinal motility disorder, a visceralsensation disorder, and a central nervous disorder. While the symptomsof IBS have a physiological basis, no physiological mechanism unique toIBS has been identified. Rather, the same mechanisms that causeoccasional abdominal discomfort in healthy individuals operate toproduce the symptoms of IBS. The symptoms of IBS are therefore a productof quantitative differences in the motor reactivity of the intestinaltract, and increased sensitivity to stimuli or spontaneous contractions.

Due to a lack of readily identifiable structural or biochemicalabnormalities in this syndrome, the medical community has developed aconsensus definition and criteria, known as the Rome criteria, to aid indiagnosis of IBS. According to the Rome criteria, IBS is indicated byabdominal pain or discomfort which is (1) relieved by defection and/or(2) associated with a change in frequency or consistency of stools, plustwo or more of the following: altered stool frequency, altered stoolform, altered stool passage, passage of mucus, and bloating or feelingof abdominal distention (Dalton, C. and Drossman, D. A., Am FamPhysician 1997 55(3):875-880). Thus, a hallmark of IBS is abdominal painthat is relieved by defecation, and which is associated with a change inthe consistency or frequency of stools. IBS may be diarrhea-predominant,constipation-predominant, or an alternating combination of both.

Persons with IBS exhibit hypersensitivity, particularly hyperalgesia, inresponse to painful distensions in the small bowel and colon and tonormal intestinal function. Furthermore, there are also increased orunusual areas of visceral pain. The abdominal pain is often poorlylocalized, and may be migratory and/or variable in nature. The pain maybe worsened by meals and reduced upon defecation. Furthermore, IBSsymptoms, including hyperalgesia, are commonly initiated or exacerbatedby stress (Dalton, C. and Drossman, D. A., Am Fam Physician 199755(3):875-880).

IBS is estimated to affect up to 20% of the adult population worldwide.Women apparently are more often affected than men, and the prevalence ofirritable bowel syndrome is lower among the elderly (Camilleri, M. andChoi, M.-G., Aliment Pharmacol Ther 1997 11(1):3-15). It also seemsclear that psychological factors, either stress or overt psychologicaldisease, modulate and exacerbate the physiological mechanisms thatoperate in IBS (Drossman, D. A. et al., Gastroenterology 198895:701-708).

Some studies suggest that only about 10% to 50% of those afflicted withIBS actually seek medical attention. Nonetheless, IBS still accounts forup to about 3.5 million physician visits per year, and is the mostcommon diagnosis in gastroenterologists' practice, accounting for about25% of all patients (Camilleri and Choi, 1997). In a study published in1993, persons afflicted with IBS were found to have more frequent doctorvisits, a lower quality of life, and to miss three times as many daysfrom work as those with no bowel symptoms (Drossman, D. A., Dig Dis Sci1993 38:1569-1580). As a consequence, persons with IBS incur higherhealth care costs than those without IBS (Talley, N. J. et al.,Gastroenterology 1995 109:1736-1741).

Attempts to treat IBS generally focus on either (1) treatments directedto the intestinal tract (so-called “end organ therapy”) or (2)treatments directed to affective disorders mediated by the CNS which areassociated with IBS (Farthing, M. J. G., Drugs 1998 56(1):11-21). Amongthe former are gut transit accelerants, such as wheat bran, solublefiber, and polycarbophil calcium, for constipation-predominant IBS;antidiarrheals, such as loperamide, diphenoxylate, and codeinephosphate, for diarrhea-predominant IBS; and anticholinergics and smoothmuscle relaxants, such as cimetropium bromide, pinaverium bromide,octilium bromide, trimebutine, and mebeverine, for diarrhea-predominantIBS and abdominal pain. In addition, alterations in diet have beentargeted for those patients with food sensitivities or food allergies.

The end organ therapy treatments for IBS have proved ineffective orcontain inherent drawbacks that limit their usefulness. For example,while the gut accelerants are useful to accelerate gut transit, theyalso exacerbate abdominal pain and bloating. Likewise, whileantidiarrheals, such as loperamide, are often effective in treatingdiarrhea-predominant IBS, they are ineffective in treating theadditional symptoms associated with IBS, such as abdominal pain. As aconsequence, end organ therapy often is limited to patients with mild ormoderate symptoms.

The anticholinergics and smooth muscle relaxants are effective inrelieving pain associated with IBS, although their effects on othersymptoms associated with IBS is unclear (Committee, Gastroenterology1997 112:2120-2137; Pace, F. et al., Digestion 1995 56:433-442). Inaddition, some of the most effective compounds in these classes are notavailable for use in the United States, since they have not beenapproved by the Federal Food and Drug Administration (Committee, 1997).Finally, dietary alterations are of limited utility for a small segmentof IBS patients.

Central nervous system treatments have received attention as potentialIBS therapies because of the well recognized link between affectivedisorders and IBS, and also because of the disturbances in bowel healththat occurs in individuals with these disorders. The tricyclicantidepressants, such as amitriptyline, imipramine, and doxepin, arefrequently used to treat IBS, due to the neuromodulatory and analgesicproperties of these compounds, which are independent of theirpsychotropic effects. However, because of their psychotropic properties,administration of these drugs requires long-term care, and are usuallyonly given to patients with severe or refractory symptoms, impaireddaily function, and associated depression or anxiety attacks.Furthermore, the newer antidepressants, in particular the specificserotonin reuptake inhibitors, such as fluoxetine, serraline, andparoxetine, have not been shown to be more effective than the tricyclicantidepressants, although some anecdotal evidence suggests thesecompounds may have fewer side effects (Committee, 1997).

Nalmefene glucuronide, an opioid receptor antagonist, has beeninvestigated as a treatment for constipation-predominant IBS (Chami, T.N., et al., Am J Gastroenterol 1993 88:1568 [abstract]). Over aneight-week period, eight patients received 16 mg nahnefene glucuronidethree times a week. While the patients reported decreased transit timeand increased stool frequency, nalmefene glucuronide did not reduceabdominal pain or bloating, and stool consistency was not improved. Thepresent inventors believe that the failure of nalmefene to treat painassociated with IBS can be attributed to the fact that this study used ahigh dose of nalmefene which antagonizes both excitatory and inhibitoryopioid receptor-mediated functions in the gut as well as in the CNS.This view is supported by recent evidence that 1,000-fold lower doses ofnalmefene (ca. 15 μg, IV) have been shown to markedly enhance morphine'sanalgesic potency (Joshi et al., Anesthesiol. 1999, in press), whereasdoses of >0.5 mg markedly attenuate opioid analgesia (Konieczko, K. M.et al., Br J Anaesth 1988 61(3):318-23).

Recent reports of successful treatment of IBS patients with high dosesof the kappa opioid agonist, fedotizine (30 mg, three times daily)(Dapoigny, M. et al., Dig Dis Sci 1995 40(10):2244-9; Gue, M. et al.,Gastroenterology 1994 107(5):1327-34) may be due to masking ofsupersensitized excitatory opioid receptor activity in the gut byactivation of inhibitory opioid receptor functions, analogous tomethadone maintenance of opioid addicts. Supersensitized excitatoryopioid receptor functions in the gut may also result in tolerance to theanalgesic effects of endogenous opioids (Wang, L. and Gintzler, A. R., JNeurochem 1995 64(3):1102-6), which could account for the abnormalvisceral pain associated with IBS.

U.S. Pat. No. 5,512,578 discloses that the analgesic potency ofbimodally-acting opioid agonists can be enhanced, and thetolerance/dependence liability reduced, upon coadministration ofultralow doses of selective excitatory opioid receptor antagonists. Asused herein, “excitatory opioid receptor antagonists” are compounds thatbind to and inactivate excitatory opioid receptors, but not inhibitoryopioid receptors, on neurons in the nociceptive pathways. Such selectiveexcitatory opioid receptor antagonists include, when administered atappropriately low doses, naloxone, naltrexone, etorphine, anddihydroetorphine. The selective excitatory opioid receptor antagonistsattenuate excitatory, but not inhibitory, opioid receptor functions innociceptive (pain) pathways of the peripheral and central nervoussystems. As a result, symptoms associated with activation of excitatoryopioid receptors, such as anti-analgesia, hyperalgesia,hyperexcitability, physical dependence and/or tolerance effects, areblocked, whereas the analgesic effects of bimodally acting opioidagonists, which are mediated by the inhibitory opioid receptors, areunmasked and thereby enhanced (see Crain, S. M. and Shen, K.-F., ProcNatl Acad Sci U S A 1995 92:10540-10544; Crain, S. M. and Shen, K.-F.,Trends Pharmacol Sci 1998 19:358-365; Ann N Y Acad Sci 1998 845:106-25;Shen, K.-F. and Crain, S. M., Brain Res 1997 757(2):176-90). Thepredictions based on these preclinical studies have been recentlyconfirmed by clinical studies on postsurgical patients whichdemonstrated that cotreatment with morphine plus low-dose naloxone ornalmefene markedly enhanced the analgesic potency of morphineadministered over 24-hour test periods (Joshi et al., Anesthesiol. 1999,in press; Gan, T. J. et al., Anesthesiol. 1997 87:1075-1081).

U.S. Pat. No. 5,512,578 further discloses that ultralow doses ofnaltrexone can, alone or in combination with low-dose methadone, provideeffective longterm maintenance treatment for opioid addiction to preventrelapse to drug abuse. Furthermore, ultralow doses of selectiveexcitatory opioid receptor antagonists can be administered alone tochronic pain patients to enhance the analgesic potency and reduce thetolerance/dependence liability of endogenous opioid peptides, such asenkephalins, dynorphins, and endorphins, which are elevated in chronicpain patients (Crain and Shen, 1995). However, there is no teaching orsuggestion in U.S. Pat. No. 5,512,578 that administration of a selectiveexcitatory opioid receptor antagonist would be useful in treatingsymptoms of lBS. In particular, there is no teaching or suggestion thatadministration of a selective excitatory opioid receptor antagonistwould be useful in treating symptoms of IBS that are unrelated to thenociceptive pathways, such as stool frequency or consistency.

U.S. Pat. No. 5,472,943 also discloses a method wherein coadministrationof an ultralow dose of a selective excitatory opioid receptor antagonistwith a bimodally-acting opioid agonist selectively enhances theanalgesic effect of the bimodally-acting opioid agonist while reducingthe undesirable side-effects associated with longterm administration ofthe opioid agonist. However, U.S. Pat. No. 5,472,943 does not disclosethat a selective excitatory opioid receptor antagonist can be used inthe absence of a bimodally-acting opioid agonist.

Both U.S. Pat. No. 5,580,876 and U.S. Pat. No. 5,767,125 also disclose amethod to selectively enhance the analgesic effect of a bimodally-actingopioid agonist while reducing unwanted side-effects associated with theadministration of the opioid agonist by coadministration of the opioidagonist with an amount of an excitatory opioid receptor antagonist, suchas naltrexone or nalmefene, effective to enhance the analgesic effect ofthe bimodally-acting opioid agonist while reducing the undesirableside-effects. U.S. Pat. No. 5,580,876 and U.S. Pat. No. 5,767,125disclose use of an excitatory opioid receptor antagonist alone fortreatment of opioid addicts, and do not teach or suggest thatadministration of a selective excitatory opioid receptor antagonistwould be useful in treating symptoms of IBS. In particular, there is noteaching or suggestion that administration of a selective excitatoryopioid receptor antagonist would be useful in treating other symptoms ofIBS, such as stool frequency or consistency.

U.S. Pat. No. 5,585,348 relates to a method for reducing hyperalgesiaassociated with administration of nerve growth factor or related growthfactors. The method comprises administration of a selective excitatoryopioid receptor antagonist prior to or simultaneously with theadministration of nerve growth factor. However, U.S. Pat. No. 5,585,348does not disclose that the selective opioid receptor antagonist may beadministered in the absence of nerve growth factor, and does not teachor suggest that the administration of a selective excitatory opioidreceptor antagonist alone would be useful in treating IBS.

SUMMARY OF THE INVENTION

The present invention is directed to a method for treating a subjectwith IBS. The method comprises administering to the patient a low doseof an opioid receptor antagonist. In addition, the present inventionprovides a pharmaceutical composition, comprising an effective dose ofan excitatory opioid receptor antagonist, and a pharmaceuticallyacceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “treating IBS” is considered to mean reducing orattenuating abdominal pain and reducing or attenuating one or more ofabnormal consistency or abnormal frequency of stools associated with IBSin a patient. The present inventors have discovered that longtermadministration of an excitatory opioid receptor antagonist can relievesymptoms associated with IBS, in particular the abdominal pain and theabnormal consistency and/or frequency of stools. Accordingly, thepresent invention is directed to a method for treating patients with IBSby longterm administration of appropriately low doses of an excitatoryopioid receptor antagonist.

The primary concept of the present invention is that since remarkablysimilar bimodal excitatory and inhibitory opioid receptor functions havebeen demonstrated to exist in myenteric neurons in the intestine (Xu, H.et al., Brain Res. 1989 504(1):36-42; Gintzler, A. R., Adv Exp Med Biol.1995 373:73-83; Wang and Gintzler, 1995) as occur in somatic sensory andCNS neurons (Shen, K.-F. and Crain, S. M., Brain Res. 1989491(2):227-42; Crain, S. M. and Shen, K.-F., Trends Pharmacol Sci. 199011(2):77-81; Crain and Shen, 1998), selective antagonism of abnormal orsupersensitized excitatory opioid receptor functions in gut neurons bylow doses of an opioid receptor antagonist may enhance the analgesiceffects of endogenous opioids on visceral sensory neurons and attenuatehypersensitivities and hyperexcitabilities of visceral sensory andvisceral motor neurons involved in IBS.

Abnormal levels of endogenous opioid peptides may be generated in thegut by emotional stress, inflammatory or metabolic disorders, orintrinsic release from gut neurons. Excitatory opioid receptors in thegut may become supersensitized by chronic exposure to endogenous orexogenous bimodally-acting (excitatory/inhibitory) opioid agonists, ashas been shown to occur in somatic sensory dorsal root ganglia (“DRG”)neurons (Crain, S. M. and Shen, K.-F., Brain Res. 1992 575:13-24; Shen,K.-F. and Crain, S. M., Brain Res 1992 597:74-83). Neurons withsupersensitized excitatory opioid receptor functions in the gut maytherefore become “physically dependent” on opioids, just as occurs insomatic sensory and CNS neurons. Selective activation of excitatoryopioid receptor functions by application of low (i.e., nM)concentrations of bimodally-acting opioid agonists to myenteric neuronsin the guinea pig ileum enhances the high-K⁺-stimulated release of theμ/δ opioid peptide, Met-enkephalin, whereas high (i.e., μM) opioidconcentrations inhibits Met-enkephalin release (Xu et al., 1989).Intermittent increases in the release of Met-enkephalin or otherendogenous opioid peptides by activation of supersensitized excitatoryopioid receptors in the gut could, therefore, exacerbate “dependence”and “withdrawal” symptoms associated with IBS via a positive-feedbackcycle analogous to mechanisms proposed to mediate protracted opioiddependence in the CNS (Crain and Shen, Brain Res1992, Crain and Shen,1998). In addition, the release of the kappa opioid peptide, dynorphin,from the peripheral (as well as central) terminals of sensory neuronsmay also play a role in mediating hyperalgesic effects in IBS, in viewof evidence obtained on DRG neurons in vitro and in vivo (Shen, K.-F.and Crain, S. M., J Neurosci 1994 14:5570-5579; Apfel, S. C. et al.,Neurosci 1995 68:1199-1206).

Excitatory opioid receptor antagonists suitable for use in the presentinvention include, but are not limited to, nalmefene, naltrexone,naloxone, etorphine and dihydroetorphine, as well as similarly actingopioid alkaloids and opioid peptides (e.g., biphalin, see Horan, P. J.et al., J Pharmacol Exp Ther. 1993 265(3):1446-54; Shen, K.-F. andCrain, S. M., Brain Res 1995 701(1-2):158-66). Preferred excitatoryopioid receptor antagonists are nahnefene and naltrexone, because oftheir increased duration of action as compared to naloxone and theirgreater bioavailability after oral administration.

Other excitatory opioid receptor antagonists suitable for use in thepresent invention may be identified by measuring their effect on theaction potential duration (“APD”) of DRG neurons in tissue cultures, asdescribed in U.S. Pat. No. 5,472,943. In particular, excitatory opioidreceptor antagonists of the present invention are compounds whichselectively block prolongation of the APD of DRG neurons induced by lowconcentrations of morphine and other bimodally acting opioids (anexcitatory opioid receptor effect), and unmask shortening of the APD (aninhibitory opioid receptor effect) in DRG neurons, which generallyrequires much higher concentrations of these bimodally-acting opioidreceptor agonists (see U.S. Pat. No. 5,472,943).

The dose of an excitatory receptor antagonist to be administered wouldvary according to the specific pharmacologic properties of the opioidreceptor antagonist employed and the characteristics of the IBS patient.For example, where the opioid receptor antagonist employed isnaltrexone, in most cases the daily dose would be in a range betweenabout 0.1 mg/day and about 5 mg/day. More preferably, the dose would bein a range between about 0.3 mg/day and about 3 mg/day. Where the opioidreceptor antagonist employed is nalmefene, in most cases the daily dosewould be in a range between about 0.01 mg/day and about 1 mg/day. Thedose administered should be sufficient to relieve the abdominal pain andother symptoms associated with IBS, but not so high as to inducedysphoria or other adverse side effects caused by sustained blockage ofinhibitory opioid receptor functions. At such a dose, the opioidreceptor antagonist binds selectively to the excitatory opioid receptorson the myenteric and CNS neurons and thereby inactivates excessiveexcitatory opioid receptor-mediated functions, such ashyperexcitability, hyperalgesia, tolerance, physical dependence, andothers. The inhibitory opioid receptor functions are not attenuated bythese low doses of the opioid receptor antagonist. As a result, theexcitatory opioid receptor antagonist treatment enhances the analgesicpotency and decreases the undesirable side effects associated withchronic activation by endogenous bimodally-acting opioid peptides,including enkephalins, dynorphins and endorphins, which are markedlyupregulated in chronic pain patients (Crain and Shen, 1995).

Naltrexone (50 mg tablets, DuPont Merck, tradenames Trexan or Revia) iscurrently approved by the FDA for longterm daily treatment of alcoholand opioid addiction. This treatment may also be effective inattenuating some types of IBS symptoms. However, at the relatively highdose employed in these treatments, naltrexone blocks all inhibitory aswell as excitatory opioid receptor functions, thereby interfering withanalgesia mediated by endogenous as well as exogenous opioids.Therefore, high-dose naltrexone or nalmefene (tradename Revex; Cheskin,L. J. et al., Drug Alcohol Depend 1995 39(2):151-4), by antagonizinginhibitory opioid receptors, will not reliably attenuate abdominal painnor intestinal dysmotility underlying changes in the consistency orfrequency of stools, and may also interfere with other importantinhibitory opioid receptormediated functions in the central nervoussystem that regulate normal emotional and euphoric states. Accordingly,low dose, selective excitatory opioid receptor antagonist therapy offersan attractive alternative that reliably attenuates abdominal pain andintestinal dysmotility underlying changes in the consistency orfrequency of stools, while retaining significant inhibitory opioidreceptor-mediated functions in the peripheral and central nervoussystem.

The excitatory opioid receptor antagonists for use in the presentinvention may be in the form of free bases or pharmaceuticallyacceptable acid addition salts thereof. Examples of suitable acids forsalt formation include but are not limited to methanesulfonic, sulfuric,hydrochloric, glucuronic, phosphoric, acetic, citric, lactic, ascorbic,maleic, and the like.

The excitatory opioid receptor antagonist may be administered to a humanor animal subject by known procedures including but not limited toorally, sublingually, parenterally, transdermally, and by suppository.

The excitatory opioid receptor antagonists may be formulated incompositions with a pharmaceutically acceptable carrier. The carriermust be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. Examples of suitable pharmaceutical carriers include lactose,sucrose, starch, talc, magnesium stearate, crystalline cellulose, methylcellulose, carboxymethyl cellulose, glycerin, sodium alginate, gumarabic, powders, saline, water, among others. The formulations mayconveniently be presented in unit dosage and may be prepared by methodswellknown in the pharmaceutical art, by bringing the active compoundinto association with a carrier or diluent, as a suspension or solution,and optionally one or more accessory ingredients, e.g. buffers,flavoring agents, surface active agents, and the like. The choice ofcarrier will depend upon the route of administration.

For oral and sublingual administration, the formulation may be presentedas capsules, tablets, powders, granules or a suspension, withconventional additives such as lactose, mannitol, corn starch or potatostarch; with binders such as crystalline cellulose, cellulosederivatives, acacia, corn starch or gelatins; with disintegrators suchas corn starch, potato starch or sodium carboxymethyl-cellulose; andwith lubricants such as talc or magnesium stearate.

For parenteral administration, the opioid receptor antagonist maycombined with a sterile aqueous solution which is preferably isotonicwith the blood of the recipient. Such formulations may be prepared bydissolving solid active ingredient in water containing physiologicallycompatible substances such as sodium chloride, glycine, and the like,and having a buffered pH compatible with physiological conditions toproduce an aqueous solution, and rendering said solution sterile. Theformulations may be present in unit or multi-dose containers such assealed ampoules or vials.

For transdermal administration, the opioid receptor antagonist may becombined with skin penetration enhancers such as propylene glycol,polyethylene glycol, isopropanol, ethanol, oleic acid,N-methylpyrrolidone, and the like, which increase the permeability ofthe skin to the compounds, and permit the compounds to penetrate throughthe skin and into the bloodstream. The antagonist/enhancer compositionsalso may be combined additionally with a polymeric substance such asethylcellulose, hydroxypropyl cellulose, ethylene/ vinylacetate,polyvinyl pyrrolidone, and the like, to provide the composition in gelform, which can be dissolved in solvent such as methylene chloride,evaporated to the desired viscosity, and then applied to backingmaterial to provide a patch.

For administration by suppository, the opioid receptor antagonist may becombined with any appropriate base to form a mass that is solid at roomtemperature but dissolves at body temperature. The base may include,without limitation, cocao butter, glycerinated gelatin, hydrogenatedvegetable oils, polyethylene glycols of various molecular weights, fattyacid esters of polyethylene glycols, and the like.

The amount of the excitatory opioid receptor antagonist administered isan amount effective to attenuate abdominal pain and intestinaldysmotility which produces changes in the consistency or frequency ofstools and thereby enhance the analgesic potency of endogenous opioidpeptide agonists in the intestinal tract and in the CNS. That is, theopioid receptor antagonist is administered at a low dose which blocksthe effects of bimodally-acting opioid peptide agonists onhigheraffinity excitatory opioid receptors without blocking the effectson inhibitory opioid receptors. This amount is readily determinable byone skilled in the art (Crain and Shen, 1995, 1998; Shen and Crain,1997).

The present invention is described in the following Clinical Study whichis set forth to aid in the understanding of the invention, and shouldnot be construed to limit in any way the invention as defined in theclaims which follow thereafter.

CLINICAL STUDY

An open study of low dose naltrexone administration in four (4) patientswith IBS was initiated. The patients were evaluated for IBS, based onthe Rome criteria. All patients were screened for other disorders ormedications that could cause gastrointestinal symptoms of IBS. Theseincluded inflammatory bowel disease, cancer, lactose intolerance, andneurological disorders, as well as the use of narcotic medications. Eachpatient was considered to be significantly incapacitated by theirsymptoms. Each subject was fully informed of the benefits and possibleside effects of the study and thereafter freely gave their consent toparticipate in the study.

Each patient maintained a daily diary of the symptoms prior to andduring treatment with 1-3 mg/day of naltrexone. Each participant notedthe following symptoms:

1. Pain, relieved by defecation

2. Stool frequency

3. Stool consistency

4. Abdominal distension

5. Passage of mucus

6. Completion of evacuation In addition, each patient was asked toglobally assess their subjective improvement on a scale of 0-4(zerocorresponding to no observable change, and 4 representing a marked andsubstantially improved state). Patients were permitted to remain onmedications other than anticholinergics and anti-diarrheal agents (i.e.,fiber bulking agents or lactose enzyme replacement if needed).

Naltrexone (tradename Revia; 50 mg tablets; DuPont Merck) was purchasedat a pharmacy. Single tablets were crushed and dissolved in 50 ml boileddistilled water, and stored unfrozen in a refrigerator. Each patientreceived 2 ml (2 mg) orally each morning with breakfast. Medication wasprepared weekly and used for seven doses, with the remainder beingdiscarded. None of the four patients reported discernible side effects.

Patient A was a 64-year-old male with lifelong symptoms of crampingabdominal pain and unformed bowel movements associated with mucus,usually in the morning, about 4-8 times per day. After nine months oftreatment, Patient A reported that stool frequency was reduced to 1-2formed bowel movements per day with no cramping abdominal pain. PatientA assessed his global improvement on the 0-4 scale as 4.

Patient B was a 71-year-old female with constipation episodesaccompanied by cramping abdominal pain over a nine-year period. After asigmoid resection for bleeding from a diverticulum two years ago, shehad 10-12 diarrheal movements per day with increased cramping that wasunresponsive to anti-diarrheals (loperamide) and a calcium carbophilbulking agent (2 tablets with meals). After 75 days of treatment,Patient B reported stool frequency was reduced to 2-4 bowel movementsper day with total elimination of abdominal pain associated withcramping. Patient B assessed her global improvement on the 0-4 scale as3.

Patient C was a 63-year-old male reporting symptoms of abdominalcramping pain, particularly at night, abdominal distension, and 2-3loose bowel movements daily. After 75 days of treatment with 2 mg/day ofnaltrexone, Patient C reported his abdominal pain associated withcramping had been eliminated, and his loose bowel movements had beenhalved in frequency. Patient C assessed his global improvement on the0-4 scale as 2.5.

Patient D was a 42-year-old male who, over a three and a half yearperiod of care, had reported 7-10 unformed diarrheal movements per day,with incapacitating abdominal cramping at various periods throughout theday. He was also known to be lactose intolerant, and was beingameliorated by a lactose free diet and enzyme replacement therapy atmeals. Patent D required daily loperamide and anticholinergics prior toinitiation of the study. Upon initiation of low dose naltrexonetreatment, Patient D reported immediate relief of abdominal crampingsymptoms and reduction in stool frequency by 50 percent. Thisimprovement has continued over a 70 day treatment period, except whenPatient D noted intake of alcoholic beverages (equivalent to ca. 25-35gin equivalent of ethyl alcohol), whereupon IBS symptoms recurred forthe next twenty-four hours. Patient D assessed his global improvement onthe 0-4 scale as 2.5.

Patients A and C both attempted to change dosing schedules to everyother day during the treatment period. In both cases, IBS symptomsreturned, and remained until the daily treatment schedule was restored.Patient A also noted a return of symptoms when he traveled and forgot topack his medication.

A followup of each patient was performed 24 months after the start ofthe study. After 24 months of treatment, Patient A was on a schedule of2.5-3.0 mg naltrexone/day, corresponding to a dose of 25-30 μg/kg bodyweight/day. Patient A reported that his abdominal cramping hadcompletely ceased, and his frequency of bowel actions had returned tonormal levels.

Patient B reported after 12 months of treatment that she was on aschedule of 1.5-2.3 mg naltrexone/day, corresponding to a dose of 30-45μg/kg body weight/day. Patient B experienced a 50% reduction inabdominal cramping, but no change in the frequency of bowel actions.

After 24 months of the study, Patient C had been diagnosed withfibromyalgia, and his IBS symptoms did not respond. Patient C had beenon a regimen of 1-2 mg naltrexone/day, corresponding to a dose of 14-27μg/kg body weight/day. Patient C refused to escalate the dose ofnaltrexone, and naltrexone was stopped after 6 months.

Patient D reported after nine months of treatment that he was on aschedule of 2.5-3.0 mg naltrexone/day, corresponding to a dose of 25-30μg/kg body weight/day. After 9 months of treatment, Patient D reported a75% decrease in cramping, and a 20% reduction in frequency of bowelactions. At this point low-dose naltrexone treatment was halted, and IBSsymptoms returned.

All publications and patents mentioned hereinabove are herebyincorporated by reference in their entirety.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of various aspects of the invention. Thus, it isto be understood that numerous modifications may be made in theillustrative embodiments and other arrangements may be devised withoutdeparting from the spirit and scope of the invention.

What is claimed is:
 1. A method for treating irritable bowel syndrome ina subject in need of such treatment, comprising administering to saidsubject an amount of an excitatory opioid receptor antagonist effectiveto treat irritable bowel syndrome in said subject.
 2. The methodaccording to claim 1, wherein said amount of the excitatory opioidreceptor antagonist is effective to block at least one ofhypersensitivity and hyperexcitability of visceral sensory and visceralmotor neurons associated with irritable bowel syndrome.
 3. The methodaccording to claim 1, wherein said amount of the excitatory opioidreceptor antagonist is effective to treat abdominal pain and at leastone of abnormal consistency and abnormal frequency of stools in saidsubject.
 4. The method according to claim 1, wherein said excitatoryopioid receptor antagonist is a member selected from the groupconsisting of naltrexone, nalmefene, diprenorphine, naloxone, etorphine,dihydroetorphine, biphalin, and similarly acting opioid alkaloids orpeptides.
 5. The method according to claim 1, wherein said excitatoryopioid receptor antagonist is naltrexone.
 6. The method according toclaim 5, wherein said naltrexone is administered at a dose effective torelieve abdominal pain associated with IBS and wherein said dose isfurther ineffective to induce dysphoria.
 7. The method according toclaim 5, wherein said naltrexone is administered at a dose between about0.1 mg/day and about 5 mg/day.
 8. The method according to claim 5,wherein said naltrexone is administered at a dose between about 0.3mg/day and about 3 mg/day.
 9. The method according to claim 5, whereinsaid naltrexone is administered at a dose between about 2 μg/kg bodyweight/day and about 70 μg/kg body weight/day.
 10. The method accordingto claim 5, wherein said naltrexone is administered at a dose betweenabout 4 μg/kg body weight/day and about 45 μg/kg body weight/day. 11.The method according to claim 1, wherein said excitatory opioid receptorantagonist is nalmefene.
 12. The method according to claim 11, whereinsaid nalmefene is administered at a dose effective to relieve abdominalpain associated with IBS and wherein said dose is further ineffective toinduce dysphoria.
 13. The method according to claim 11, wherein saidnalmefene is administered at a dose between about 0.01 mg/day and about1 mg/day.
 14. The method according to claim 1, wherein said excitatoryopioid receptor antagonist is administered in one or more forms selectedfrom the group consisting of orally, parenterally, transdermally, or bysuppository.
 15. The method according to claim 1, wherein saidexcitatory opioid receptor antagonist is administered orally.